Blockage of the Na-K-ATPase signaling-mediated oxidant amplification loop elongates red blood cell half-life and ameliorates uremic anemia induced by 5/6th PNx in C57BL/6 mice.

ABSTRACT

We have previously demonstrated that the Na-K-ATPase signaling-mediated oxidant amplification loop contributes to experimental uremic cardiomyopathy and anemia induced by 5/6th partial nephrectomy (PNx). This process can be ameliorated by systemic administration of the peptide pNaKtide, which was designed to block this oxidant amplification loop. The present study demonstrated that the PNx-induced anemia is characterized by marked decreases in red blood cell (RBC) survival as assessed by biotinylated RBC clearance and eryptosis as assessed by annexin V binding. No significant change in iron homeostasis was observed. Examination of plasma samples demonstrated that PNx induced significant increases in systemic oxidant stress as assessed by protein carbonylation, plasma erythropoietin concentration, and blood urea nitrogen. Systemic administration of pNaKtide, but not NaKtide (pNaKtide without the TAT leader sequence) and a scramble "pNaKtide" (sc-pNaKtide), led to the normalization of hematocrit, RBC survival, and plasma protein carbonylation. Administration of the three peptides had no significant effect on PNx-induced increases in plasma erythropoietin and blood urea nitrogen without notable changes in iron metabolism. These data indicate that blockage of the Na-K-ATPase signaling-mediated oxidant amplification loop ameliorates the anemia of experimental renal failure by increasing RBC survival.NEW & NOTEWORTHY The anemia of CKD is multifactorial, and the current treatment based primarily on stimulating bone marrow production of RBCs with erythropoietin or erythropoietin analogs is unsatisfactory. In a murine model of CKD that is complicated by anemia, blockade of Na-K-ATPase signaling with a specific peptide (pNaKtide) ameliorated the anemia primarily by increasing RBC survival. Should these results be confirmed in patients, this strategy may allow for novel and potentially additive strategies to treat the anemia of CKD.